title: The TLR7 ligand 9-benzyl-2-butoxy-8-hydroxy adenine inhibits IL-17 response by eliciting IL-10 and IL-10-inducing cytokines.
abstract: This study evaluates the ability of a novel TLR7 ligand (9-benzyl-2-butoxy-8-hydroxy adenine, called SA-2) to affect IL-17 response. The SA-2 activity on the expression of IL-17A and IL-17-related molecules was evaluated in acute and chronic models of asthma as well as in in vivo and in vitro α-galactosyl ceramide (α-GalCer)-driven systems. SA-2 prepriming reduced neutrophils in bronchoalveolar lavage fluid and decreased methacoline-induced airway hyperresponsiveness in murine asthma models. These results were associated with the reduction of IL-17A (and type 2 cytokines) as well as of molecules favoring Th17 (and Th2) development in lung tissue. The IL-17A production in response to α-GalCer by spleen mononuclear cells was inhibited in vitro by the presence of SA-2. Reduced IL-17A (as well as IFN-γ and IL-13) serum levels in mice treated with α-GalCer plus SA-2 were also observed. The in vitro results indicated that IL-10 produced by B cells and IL-10-promoting molecules such as IFN-α and IL-27 by dendritic cells are the major player for SA-2-driven IL-17A (and also IFN-γ and IL-13) inhibition. The in vivo experiments with anti-cytokine receptor Abs provided evidence of an early IL-17A inhibition essentially due to IL-10 produced by resident peritoneal cells and of a delayed IL-17A inhibition sustained by IFN-α and IL-27, which in turn drive effector T cells to IL-10 production. These findings suggest that such TLR7 agonist downregulating Th17 (as well as Th2) response has to be considered a valid candidate for novel vaccine formulations in allergy.
authors.affiliation: Immunoallergology Unit, Careggi Hospital, 50134 Florence, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vultaggio
authors.forename: Francesca
authors.initials: F
authors.lastname: Nencini
authors.forename: Sara
authors.initials: S
authors.lastname: Pratesi
authors.forename: Laura
authors.initials: L
authors.lastname: Maggi
authors.forename: Antonio
authors.initials: A
authors.lastname: Guarna
authors.forename: Francesco
authors.initials: F
authors.lastname: Annunziato
authors.forename: Sergio
authors.initials: S
authors.lastname: Romagnani
authors.forename: Paola
authors.initials: P
authors.lastname: Parronchi
authors.forename: Enrico
authors.initials: E
authors.lastname: Maggi
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D018793:Interleukin-13 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000378:metabolism
chemical_list: C559870:9-benzyl-2-butoxy-8-hydroxyadenine; D016207:Cytokines; D005699:Galactosylceramides; D018793:Interleukin-13; D020381:Interleukin-17; D051199:Toll-Like Receptor 7; C493154:alpha-galactosylceramide; D016753:Interleukin-10; D007371:Interferon-gamma; D000225:Adenine